U.S. patent application number 12/237398 was filed with the patent office on 2010-11-04 for integrated flow cell with semiconductor oxide tubing.
This patent application is currently assigned to AGILENT TECHNOLOGIES, INC.. Invention is credited to Timothy BEERLING, Karsten KRAICZEK, Beno MUELLER.
Application Number | 20100277722 12/237398 |
Document ID | / |
Family ID | 43030127 |
Filed Date | 2010-11-04 |
United States Patent
Application |
20100277722 |
Kind Code |
A1 |
KRAICZEK; Karsten ; et
al. |
November 4, 2010 |
INTEGRATED FLOW CELL WITH SEMICONDUCTOR OXIDE TUBING
Abstract
An integrated flow cell, the flow cell comprising a
semiconductor substrate, and a fluidic conduit having an at least
partially transparent semiconductor oxide tubing, wherein the
semiconductor oxide tubing is formed with the semiconductor
substrate.
Inventors: |
KRAICZEK; Karsten;
(Waldbronn, DE) ; MUELLER; Beno; (Ettlingen,
DE) ; BEERLING; Timothy; (Los Angeles, CA) |
Correspondence
Address: |
Agilent Technologies, Inc. in care of:;CPA Global
P. O. Box 52050
Minneapolis
MN
55402
US
|
Assignee: |
AGILENT TECHNOLOGIES, INC.
Loveland
CO
|
Family ID: |
43030127 |
Appl. No.: |
12/237398 |
Filed: |
September 25, 2008 |
Current U.S.
Class: |
356/244 ;
204/452; 204/461; 257/E21.002; 422/70; 422/82.05; 422/89;
438/104 |
Current CPC
Class: |
B81B 2203/0338 20130101;
B81C 1/00071 20130101; B81B 2201/058 20130101; H01L 31/101
20130101; G01N 30/74 20130101; B81B 2203/0392 20130101 |
Class at
Publication: |
356/244 ;
422/82.05; 422/70; 204/452; 204/461; 422/89; 438/104;
257/E21.002 |
International
Class: |
G01N 21/01 20060101
G01N021/01; G01N 30/74 20060101 G01N030/74; G01N 21/05 20060101
G01N021/05; G01N 27/26 20060101 G01N027/26; H01L 21/02 20060101
H01L021/02 |
Claims
1. An integrated flow cell, comprising a semiconductor substrate; a
fluidic conduit having an at least partially transparent
semiconductor oxide tubing, wherein the semiconductor oxide tubing
is formed with the semiconductor substrate.
2. The flow cell according to claim 1, comprising at least one of:
the semiconductor substrate is a silicon substrate and the
semiconductor oxide tubing is a silicon oxide tubing; the
semiconductor substrate is a monocrystalline substrate; the
semiconductor oxide tubing is at least partially embedded in the
semiconductor substrate; the semiconductor oxide tubing has a
rectangular cross section; the semiconductor oxide tubing has a
hexagonal cross section; a surface of the semiconductor oxide
tubing is lined with a reflection layer adapted so that an
electromagnetic radiation beam propagating through the fluidic
conduit is totally reflected at the reflection layer; a surface of
the semiconductor oxide tubing is lined with a reflection layer
adapted so that an electromagnetic radiation beam propagating
through the fluidic conduit is totally reflected at the reflection
layer, wherein the reflection layer comprises
polytetrafluoroethylene; an inner surface of the semiconductor
oxide tubing is lined with a reflection layer adapted so that an
electromagnetic radiation beam propagating through the fluidic
conduit is totally reflected at the reflection layer; an outer
surface of the semiconductor oxide tubing is lined with a
reflection layer adapted so that an electromagnetic radiation beam
propagating through the fluidic conduit is totally reflected at the
reflection layer; the flow cell comprises a plurality of
independently operable fluidic conduits each delimited by a
semiconductor oxide tubing connected to a common semiconductor
substrate; the flow cell is adapted to conduct a fluidic sample
with a high pressure; the flow cell is adapted to conduct a fluidic
sample with a pressure of at least 50 bar, particularly of at least
100 bar, more particularly of at least 500 bar, still more
particularly of at least 1000 bar; the flow cell is adapted to
conduct a liquid sample; the flow cell is adapted as a microfluidic
flow cell; the flow cell is adapted as a nanofluidic flow cell; the
flow cell is a monolithically integrated flow cell, wherein the
semiconductor oxide tubing is monolithically formed with the
semiconductor substrate.
3. The flow cell according to claim 1, wherein the semiconductor
oxide tubing has a tubular section and has a planar section, the
tubular section delimiting the fluidic conduit and the planar
section defining a beginning and an end of the fluidic conduit in
the semiconductor substrate.
4. The flow cell according to claim 1, wherein the semiconductor
oxide tubing is optically transparent.
5. The flow cell according to claim 1, wherein the semiconductor
oxide tubing is adapted so that an electromagnetic radiation beam
propagating through the fluidic conduit is totally reflected at the
semiconductor oxide tubing.
6. The flow cell according to claim 1, comprising an
electromagnetic radiation source adapted for generating an
electromagnetic radiation beam and for coupling the electromagnetic
radiation beam into the fluidic conduit.
7. The flow cell according to claim 6, comprising at least one of:
the electromagnetic radiation source is adapted for generating one
of an optical light beam and an ultraviolet beam; the flow cell
comprises an electromagnetic radiation detector adapted for
detecting the electromagnetic radiation beam after propagation
through the fluidic conduit; the flow cell comprises an
electromagnetic radiation detector adapted for detecting the
electromagnetic radiation beam after propagation through the
fluidic conduit, wherein the electromagnetic radiation detector
comprises one of an optical light detector, and an ultraviolet
radiation detector.
8. The flow cell according to claim 1, comprising a first window
element being transparent for electromagnetic radiation and being
located at a first end portion of the fluidic conduit, and
comprising a second window element being transparent for
electromagnetic radiation and being located at a second end portion
of the fluidic conduit opposing the first end portion.
9. The flow cell according to claim 8, wherein the electromagnetic
radiation source is adapted for coupling the electromagnetic
radiation beam into the fluidic conduit via the first window
element.
10. The flow cell according to claim 6, comprising at least one of:
the flow cell comprises a first optical coupler element,
particularly an optical fiber piece, arranged between the
electromagnetic radiation source and the fluidic conduit to couple
the electromagnetic radiation from the electromagnetic radiation
source into the fluidic conduit; the flow cell comprises a second
optical coupler element, particularly an optical fiber piece,
arranged between the fluidic conduit and an electromagnetic
radiation detector to couple the electromagnetic radiation from the
fluidic conduit into the electromagnetic radiation detector.
11. The flow cell according to claim 7, wherein the electromagnetic
radiation detector is adapted for receiving the electromagnetic
radiation beam from the fluidic conduit via the second window
element.
12. The flow cell according to claim 1, comprising a fluid supply
hole formed in the semiconductor oxide tubing for supplying a
fluidic sample to the fluidic conduit.
13. The flow cell according to claim 12, comprising at least one
of: the fluid supply hole is adapted for a fluidic connection to a
processing element, particularly a separation column; the fluid
supply hole is also formed in the semiconductor substrate for
supplying the fluidic sample to the fluidic conduit.
14. The flow cell according to claim 1, comprising a fluid drain
hole formed in the semiconductor oxide tubing for draining a
fluidic sample from the fluidic conduit.
15. The flow cell according to claim 14, wherein the fluid drain
hole is also formed in the semiconductor substrate for draining the
fluidic sample from the fluidic conduit.
16. A fluidic device for measuring a fluidic sample, the fluidic
device comprising a processing unit adapted for processing the
fluidic sample; a flow cell according to claim 1 in fluid
communication with the processing unit for receiving the processed
fluidic sample from the processing unit.
17. The fluidic device according to claim 16, comprising at least
one of: the processing element is adapted for retaining the fluidic
sample being a part of a mobile phase and for allowing other
components of the mobile phase to pass the processing element; the
processing element comprises a separation column; the processing
element comprises a chromatographic column for separating
components of the fluidic sample; at least a part of the processing
element is filled with a fluid separating material; at least a part
of the processing element is filled with a fluid separating
material, wherein the fluid separating material comprises beads
having a size in the range of 1 .mu.m to 50 .mu.m; at least a part
of the processing element is filled with a fluid separating
material, wherein the fluid separating material comprises beads
having pores having a size in the range of 0.02 .mu.m to 0.03
.mu.m; the flow cell is arranged downstream of the processing unit;
the processing unit comprises a plurality of planar layers
laminated to one another; the processing unit comprising a
microstructured body and porous material covering at least a
portion of a surface of the microstructured body; the fluidic
device is adapted as a fluid separation system for separating
compounds of the fluidic sample; the fluidic device is adapted to
analyze at least one physical, chemical and/or biological parameter
of at least one compound of the fluidic sample; the fluidic device
comprises at least one of the group consisting of a sensor device,
a test device for testing a device under test or a substance, a
device for chemical, biological and/or pharmaceutical analysis, a
capillary electrophoresis device, a liquid chromatography device,
an HPLC device, a gas chromatography device, and a gel
electrophoresis device.
18. A method of manufacturing an integrated flow cell, the method
comprising providing a semiconductor substrate; forming a fluidic
conduit having an at least partially transparent semiconductor
oxide tubing, wherein the semiconductor oxide tubing is formed with
the semiconductor substrate.
19. The method according to claim 18, comprising at least one of:
the method comprises forming the semiconductor oxide tubing by
converting a part of the semiconductor substrate from semiconductor
material into semiconductor oxide material; the method comprises
forming the semiconductor oxide tubing by thermally annealing a
surface of the semiconductor substrate; the method comprises
forming the semiconductor oxide tubing by deposition of
semiconductor oxide material on a surface of the semiconductor
substrate; the method comprises patterning the semiconductor
substrate before forming the semiconductor oxide tubing; the method
comprises patterning the semiconductor substrate by anisotropic
etching of material of the semiconductor substrate before forming
the semiconductor oxide tubing; the method comprises patterning the
semiconductor substrate by mechanically weakening a surface portion
of the semiconductor substrate and subsequently removing the
mechanically weakened surface portion; the method comprises
patterning the semiconductor substrate by mechanically weakening a
surface portion of the semiconductor substrate and subsequently
removing the mechanically weakened surface portion, wherein the
surface portion of the semiconductor substrate is mechanically
weakened by forming a comb-shaped structure in the surface portion
and by subsequently oxidizing the comb-shaped structure; the method
comprises patterning the semiconductor substrate by anisotropic
etching along a <100> plane before forming the semiconductor
oxide tubing to thereby form a trapezoidal recess in the
semiconductor substrate; the method comprises patterning the
semiconductor substrate by anisotropic etching along a <100>
plane before forming the semiconductor oxide tubing to thereby form
a trapezoidal recess in the semiconductor substrate, wherein the
semiconductor substrate is patterned by the anisotropic etching
along the <100> plane so that slanted side walls of the
trapezoidal recess correspond to a <111> plane of the
semiconductor substrate; the method comprises forming the
semiconductor oxide tubing in a recess of the semiconductor
substrate formed by patterning the semiconductor substrate, and
bonding two semiconductor substrates both having a semiconductor
oxide tubing in a recess in such a manner that the recesses
together form the fluidic conduit; the method comprises forming the
semiconductor oxide tubing in a recess of the semiconductor
substrate formed by patterning the semiconductor substrate, and
bonding two semiconductor substrates both having a semiconductor
oxide tubing in a recess in such a manner that the recesses
together form the fluidic conduit, further comprising selectively
removing a part of the material of at least one of the two
semiconductor substrates; the method comprises forming the
semiconductor oxide tubing in a recess of the semiconductor
substrate formed by patterning the semiconductor substrate, and
bonding two semiconductor substrates both having a semiconductor
oxide tubing in a recess in such a manner that the recesses
together form the fluidic conduit, further comprising selectively
removing a part of the material of at least one of the two
semiconductor substrates, wherein selectively removing the part of
the material of the at least one of the two semiconductor
substrates is performed by etching, particularly by wet etching;
the method comprises lining a surface, particularly an inner
surface, of the semiconductor oxide tubing with a reflection layer
adapted so that an electromagnetic radiation beam propagating
through the fluidic conduit is totally reflected at the reflection
layer; the method comprises lining a surface, particularly an inner
surface, of the semiconductor oxide tubing with a reflection layer
adapted so that an electromagnetic radiation beam propagating
through the fluidic conduit is totally reflected at the reflection
layer, wherein the lining comprises conducting a lining material
through the fluidic conduit and solidifying, particularly by
sintering, the conducted lining material at an inner wall of the
fluidic conduit to thereby form the reflection layer; the method
comprises forming a cover structure covering an outer surface of
the semiconductor oxide tubing, the cover structure having a
refraction index being smaller than a refraction index of the
semiconductor oxide tubing; the semiconductor oxide is formed based
on the semiconductor.
Description
BACKGROUND ART
[0001] The present invention relates to a flow cell.
[0002] In liquid chromatography, a fluidic analyte may be pumped
through conduits and a column comprising a material which is
capable of separating different components of the fluidic analyte.
Such a material, so-called beads which may comprise silica gel, may
be filled into a column tube which may be connected to other
elements (like a control unit, containers including sample and/or
buffers) by conduits.
[0003] When a fluidic sample is pumped through the column tube, it
is separated into different fractions. The separated fluid may be
pumped in a flow cell in which the different components are
identified on the basis of an optical detection mechanism.
[0004] U.S. Pat. No. 5,153,679 discloses an apparatus for measuring
light absorbance in a liquid sample which includes a light source
for directing light into a sample cell, a cylindrical sample cell,
a light detector for measuring intensity of light emitted from the
cell and focusing means for forming a tapered light beam to pass
through the sample cell. The tapered light beam can be either a
diverging beam or a converging beam through the cell. When the
light beam is a diverging beam, a masking means is positioned
downstream of the cell to assure that any light striking the cell
wall is not directed to the light detector.
[0005] Further conventional flow cells are disclosed in US
2003/0076491, US 2008/0079942, US 2007/0097361, US 2007/0132230, US
2007/0132241, US 2007/0132229, and WO 2007/009492.
[0006] K. Mogensen, J. El-Ali, A. Wolff, J. Kutter, "Integration of
polymer waveguides for optical detection in microfabricated
chemical analysis systems", Applied Optics, Vol. 42, No. 19, 2003,
pp. 4072 to 4079, discloses multimode polymer waveguides and
fiber-to-waveguide couplers integrated with microfluidic channels
by use of a single-mask-step procedure, which ensures
self-alignment between the optics and the fluidics.
[0007] Conventional flow cells may be complex in manufacture.
Typical dimensions of the flow path of a conventional HPLC-UV/Vis
absorption cell, as stated in U.S. Pat. No. 5,153,679, are 10 mm
length, 1 mm diameter and about 8 micro liters volume. The flow
path is not always cylindrical, it may also have a conical shape,
for instance a taper cell. The dimensions of these cells often
require special machining methods in manufacturing, for example
such as electric discharge machining, which has limited geometrical
accuracy. But in order to avoid the undesired refractive index
effects, as described in the source above, small tolerances are
required. Spark eroding also can introduce unwanted electrode
atoms, for example copper atoms, into the cell body material. The
copper atoms can lead to spurious signals when the cell is used
with extremely sensitive detectors, for example mass spectrometers.
To achieve better chromatographic resolution in HPLC, capillary LC
or CE, the cell volumes have to become smaller and hence their
inside diameters. In U.S. Pat. No. 5,184,192 A, liquid waveguide
cells with typical inside diameters in the range from 0.5 mm to
0.05 mm are described. The manufacturing of these type of cells
with such small geometries and reflecting walls require special and
complex procedures. Coatings of fluoropolymers like Teflon AF are
used to achieve total internal reflection. The coatings are
manufactured by series of filling the cell with a Teflon AF
solution followed by drying and baking processes or by complex
alternative methods.
DISCLOSURE
[0008] It is an object of the invention to provide a flow cell
which can be manufactured with reasonable effort (particularly flow
cells with very low volumes, for instance <1 micro liter). The
object is solved by the independent claims. Further embodiments are
shown by the dependent claims.
[0009] According to an exemplary embodiment of the present
invention, an at least partially (for instance monolithically)
integrated flow cell is provided, the flow cell comprising a
semiconductor substrate, and a fluidic conduit having an at least
partially transparent semiconductor oxide tubing, wherein the
semiconductor oxide tubing is (for instance monolithically) formed
with the semiconductor substrate.
[0010] According to another exemplary embodiment, a fluidic device
for measuring a fluidic sample is provided, the fluidic device
comprising a processing unit adapted for processing the fluidic
sample, and a flow cell having the above mentioned features in
fluid communication with the processing unit for receiving the
processed fluidic sample from the processing unit.
[0011] According to still another exemplary embodiment, a method of
manufacturing an (for instance monolithically) integrated flow cell
is provided, the method comprising providing a semiconductor
substrate, and forming a fluidic conduit having an at least
partially transparent semiconductor oxide tubing, wherein the
semiconductor oxide tubing is (for instance monolithically) formed
with the semiconductor substrate.
[0012] According to an exemplary embodiment, a flow cell for a
fluidic device may be provided which flow cell can be manufactured
in (for instance monolithically) integrated semiconductor
technology. Thus, it is possible that the flow cell is at least
partially formed from a common block of semiconductive material
such as a silicon wafer. Such an integrated flow cell may comprise
a fluidic conduit such as a channel which may be delimited by an
optically transparent tubing manufacturable of a semiconductor
oxide material which may originate from a part of the material of
the semiconductor substrate in which the flow cell is (for instance
monolithically) integrated. Thus, material of the semiconductor
substrate may be chemically converted to produce a for instance
optically transparent fluidic conduit tubing, or a patterned
surface of the semiconductor material may be used as a template for
growing a corresponding semiconductor oxide tubing. Thus, with
reasonable effort, it is possible to manufacture a miniaturized
flow cell which can be adapted to accommodate a fluidic sample
which can be conducted through the semiconductor oxide tubing for
instance for optical detection purposes. While the fluidic sample
flows through the semiconductor oxide tubing, an optical detection
along the longitudinal axis of the semiconductor oxide tubing may
be made possible, in a similar manner as known by conventional flow
cells. Such an integrated flow cell may be implemented in a fluid
separation apparatus such as a liquid chromatography apparatus and
may allow to reduce a size such a detection cell while being
simultaneously capable of withstanding high pressures.
[0013] In the following, further exemplary embodiments of the flow
cell will be explained. However, these embodiments also apply to
the fluidic device and the method.
[0014] The semiconductor substrate may be a silicon substrate and
the semiconductor oxide tubing may be a silicon oxide tubing. Using
the material configuration silicon/silicon oxide (SiO.sub.2) may be
particularly advantageous for the flow cell, since silicon
technology is a well established technology and silicon oxide has
the advantageous property of being optically transparent and
chemically inert, thereby making the material appropriate for
optical flow cell applications. Moreover, it is possible to convert
silicon material into silicon oxide material, for instance by
thermal oxidation, or to use the silicon material as a template for
growing silicon oxide thereon. However, alternatively, other
group-IV semiconductors may be used, such as germanium. It is also
possible that group-III group-V semiconductors are used for this
purpose, for instance gallium arsenide.
[0015] The semiconductor substrate may be a monocrystalline
substrate. The term "monocrystalline" may denote a single crystal
or crystalline solid in which the crystal lattice of the entire
sample is continuous, basically without grain boundaries. The
opposite of a single crystal sample is an amorphous structure where
the atomic position is limited to short range order only. Using a
monocrystalline substrate may allow to make use of a possible
asymmetry of the mechanical stability of such a substrate along the
different crystal axis. For instance, this may allow to
anisotropically etch recesses in a monocrystalline substrate to
thereby form the geometrical basis for subsequently forming the
tubing.
[0016] The semiconductor oxide tubing may have a rectangular cross
section. Thus, the fluid flow may be through an essentially
rectangular tubing which allows to manufacture the flow cell with
reasonable effort. A rectangular cross section may be the result of
the formation of a rectangular trench in two substrates to be
bonded.
[0017] Alternatively, the semiconductor oxide tubing may have a
hexagonal cross section. Such a hexagonal cross section may be
formed making use of the crystal anisotropy of a monocrystalline
silicon substrate used as a basis for the flow cell. It is possible
to etch a trapezoidal recess in a surface of such a monocrystalline
silicon substrate. Bonding two substrates processed in the
described way in a manner that the two trapezoidal recesses are
aligned to one another allows to manufacture such a hexagonal cross
section.
[0018] The semiconductor oxide tubing may have a tubular section
and may have a planar section, the tubular section delimiting the
fluidic conduit and the planar section defining a beginning and an
end of the fluidic conduit in the semiconductor substrate. Thus,
the planar sections may define transparent end plates through which
an optical detection may be performed.
[0019] The semiconductor oxide tubing may be optically transparent.
In other words, it is possible that the semiconductor oxide tubing
is transparent for electromagnetic radiation in the visible range,
i.e. between 400 nm and 800 nm. Additionally or alternatively, it
is possible that the semiconductor oxide tubing is optically
transparent for ultraviolet radiation, infrared radiation, or any
other wavelength range of electromagnetic radiation used for
detection purposes.
[0020] The semiconductor oxide tubing may be adapted so that an
electromagnetic radiation beam propagating through the fluidic
conduit is totally reflected at the semiconductor oxide tubing (for
instance at an inner or an outer surface thereof). Total reflection
may be advantageous, because this may guarantee that basically all
rays used for detection purposes remain within the detection cell
and contribute to the detection signal. Total reflection may be
denoted as a phenomenon that photons entirely reflect off the
surface when the photons propagate from a medium of a high index of
refraction towards a medium of a lower index of refraction. For
example, total reflection may occur when passing light from glass
to air, but not when passing light from air to glass.
[0021] A surface of the semiconductor oxide tubing may be lined
with a reflection layer adapted so that an electromagnetic
radiation beam propagating through the fluidic conduit is totally
reflected at the reflection layer. Providing such a reflection
layer, for instance made from fluoropolymers (Teflon.RTM. AF) at an
inner surface of the semiconductor oxide tubing may allow to
further increase the efficiency of the usage of the electromagnetic
radiation beams.
[0022] Additionally or alternatively, it is also possible that an
outer surface of the semiconductor oxide tubing is lined with a
reflection layer adapted so that an electromagnetic radiation beam
propagating through the fluidic conduit is totally reflected at the
reflection layer. Hence, also an outer surface may be lined, which
may be made possible by correspondingly adjusting the refraction
indices of the material of the semiconductor oxide tubing and the
reflection layer to fulfill the condition that total reflection is
only possible at a boundary from a medium with a higher refractive
index to a medium with a lower refractive index.
[0023] The flow cell may comprise an electromagnetic radiation
source adapted for generating an electromagnetic radiation beam and
for coupling the electromagnetic radiation beam into the fluidic
conduit. Such an electromagnetic radiation source may be a light
emitting diode, a laser, a light bulb, or any other electromagnetic
radiation source having an appropriate emission wavelength or
emission wavelength range. Such an electromagnetic radiation may be
coupled into the fluidic conduit delimited by the semiconductor
oxide tubing.
[0024] The electromagnetic radiation source may be adapted for
generating an optical light beam (for instance having a wavelength
between about 400 nm and about 800 nm) or an ultraviolet (UV) beam
(having shorter wavelengths). The miniature dimensions of the flow
cell according to an exemplary embodiment may be appropriate not
only for optical applications but also for UV applications,
generally for UV-Vis applications.
[0025] The flow cell may comprise an electromagnetic radiation
detector adapted for detecting the electromagnetic radiation beam
after propagation through the fluidic conduit. Such an
electromagnetic radiation detector may be arranged to detect light
after traveling through the fluidic conduit. Such an
electromagnetic radiation detector, for instance a light detector,
may comprise a photodiode, a photodiode array or the like capable
of generating an electric signal indicative of the corresponding
optical signal. It is possible that such an electromagnetic
radiation detector comprises a linear or two-dimensional array of
photosensitive elements. Such an electromagnetic radiation detector
may further comprise additional optical elements such as a grating
or the like.
[0026] The electromagnetic radiation detector may comprise an
optical light detector and/or an ultraviolet radiation detector.
The range of sensitivity regarding wavelength of the
electromagnetic radiation detector may therefore be adapted to the
wavelength of the light used for exciting the system. For instance,
the detector may measure electromagnetic radiation absorption by
the fluidic sample, electromagnetic radiation reflection by the
fluidic sample, electromagnetic radiation fluorescence of the
fluidic sample, etc.
[0027] The flow cell may comprise a first window element being
transparent for electromagnetic radiation and being located at a
first end portion of the fluidic conduit, and may comprise a second
window element being transparent for electromagnetic radiation and
being located at a second end portion of the fluidic conduit
opposing the first end portion. Such window elements may define the
portions at which the electromagnetic radiation beam is coupled in
and is coupled out of the system. Such window elements may be
optically transparent end plates having a planar surface which is
oriented perpendicular to a direction of the fluid flow.
[0028] The electromagnetic radiation source may be adapted for
coupling the electromagnetic radiation beam into the fluidic
conduit via the first window element. Thus, the beam generated by
the electromagnetic radiation source may propagate through the
first window element, from there via total internal reflection
through the fluidic conduit defined by the semiconductor oxide
tubing, and may leave the optical path via the second window
element, to be subsequently directed onto the detector.
[0029] The flow cell may further comprise a first optical coupler
element arranged between the electromagnetic radiation source and
the fluidic conduit to couple the electromagnetic radiation from
the electromagnetic radiation source into the fluidic conduit. Such
a first optical coupler element may be an optical fiber which may
be inserted in a manner so as to sandwich the first window with the
semiconductor oxide tubing, and a second optical coupler element
may be arranged between the semiconductor oxide tubing on the one
hand and the detector on the other hand to provide for a symmetric
configuration. Via such optical fiber pieces (such as a light
fiber) or any other waveguides, it is possible to precisely control
the optical path to thereby achieve an optimum of light efficiency,
or in other words to keep the light loss as small as possible.
[0030] The flow cell may further comprise a fluid supply hole
formed in the semiconductor oxide tubing for supplying the fluidic
sample from a connected fluidic component to the fluidic conduit.
Such a fluid supply hole may be formed as a bore in the
semiconductor substrate and may have an orientation essentially
perpendicular to a fluid flow direction of the fluidic conduit. Via
the fluid supply hole, a fluidic sample, for instance originating
from an outlet of a separation column such as a chromatographic
column, may be injected into the fluidic conduit for detection
purposes. Thus, the fluid supply hole may be adapted for a fluidic
connection to a processing element, particularly a separation
column. A sealing of the fluid traveling via the fluid supply hole
through the fluidic conduit may be realized by a press seal
configuration, such as a hole-to-hole connection between the fluid
supply hole in the flow cell and the column. The fluid supply hole
may be formed in the semiconductor substrate for supplying the
fluidic sample to the fluidic conduit.
[0031] The flow cell may further comprise a fluid drain hole formed
in the semiconductor oxide tubing for draining the fluidic sample
from the fluidic conduit. The fluid drain hole may be arranged
symmetrically to the fluid supply hole and may be formed with a
similar technology in another end portion of the semiconductor
oxide tubing. It may also be formed in the semiconductor substrate
for draining the fluidic sample from the fluidic conduit and may
guide the separated and detected fluidic sample to a fractioner, a
waste container or the like.
[0032] The flow cell may comprise a plurality of independently
operable fluidic conduits each delimited by a semiconductor oxide
tubing connected to a common semiconductor substrate. Thus,
multiple optical and fluid flow paths may be formed in a shared
semiconductor substrate for separate (for instance parallel)
operation. This may allow to parallelize fluid analysis operations
such as fluid separation analysis, to provide for high throughput
applications.
[0033] M. Najmzadeh, S. Haasl, P. Enoksson, "A Straight Silicon
Tube as a Microfluidic Density Sensor", Proceedings of the 11th
international conference on miniaturized systems for chemistry and
life sciences pp. 536-538, No. 47833 discloses a density sensor
based on a silicon straight tube. Corresponding manufacturing
methods may be implemented according to exemplary embodiments for
manufacturing flow cells.
[0034] In the following, further exemplary embodiments of the
fluidic device will be explained. However, these embodiments also
apply to the detector device and the method.
[0035] The fluidic device may comprise a processing element filled
with a separating material. Such a separating material which may
also be denoted as a stationary phase may be any material which
allows an adjustable degree of interaction with a sample so as to
be capable of separating different components of such a sample. The
processing element may be arranged in a fluidic path upstream the
detector so that fractions of a sample separated by the processing
element may be subsequently detected by the detector device.
[0036] The separating material may be a liquid chromatography
column filling material or packing material comprising at least one
of the group consisting of polystyrene, zeolite, polyvinylalcohol,
polytetrafluorethylene, glass, polymeric powder, silicon dioxide,
and silica gel, or any of above with chemically modified (coated,
capped etc) surface. However, any packing material can be used
which has material properties allowing an analyte passing through
this material to be separated into different components, for
instance due to different kinds of interactions or affinities
between the packing material and fractions of the analyte.
[0037] At least a part of the processing element may be filled with
a fluid separating material, wherein the fluid separating material
may comprise beads having a size in the range of essentially 1
.mu.m to essentially 50 .mu.m. Thus, these beads may be small
particles which may be filled inside the separation section of the
microfluidic device. The beads may have pores having a size in the
range of essentially 0.01 .mu.m to essentially 0.2 .mu.m. The
fluidic sample may be passed through the pores, wherein an
interaction may occur between the fluidic sample and the pores.
[0038] The fluidic device may be adapted as a fluid separation
system for separating components of the sample. When a mobile phase
including a fluidic sample passes through the fluidic device, for
instance with a high pressure, the interaction between a filling of
the column and the fluidic sample may allow for separating
different components of the sample, as performed in a liquid
chromatography device.
[0039] However, the fluidic device may also be adapted as a fluid
purification system for purifying the fluidic sample. By spatially
separating different fractions of the fluidic sample, a
multi-component sample may be purified, for instance a protein
solution. When a protein solution has been prepared in a
biochemical lab, it may still comprise a plurality of components.
If, for instance, only a single protein of this multi-component
liquid is of interest, the sample may be forced to pass the column.
Due to the different interaction of the different protein fractions
with the filling of the column (for instance using a liquid
chromatography device), the different samples may be distinguished,
and one sample or band of material may be selectively isolated as a
purified sample.
[0040] The fluidic device may be adapted to analyze at least one
physical, chemical and/or biological parameter of at least one
component of the mobile phase. The term "physical parameter" may
particularly denote a size or a temperature of the fluid. The term
"chemical parameter" may particularly denote a concentration of a
fraction of the analyte, an affinity parameter, or the like. The
term "biological parameter" may particularly denote a concentration
of a protein, a gene or the like in a biochemical solution, a
biological activity of a component, etc.
[0041] The fluidic device may be implemented in different technical
environments, like a sensor device, a test device, a device for
chemical, biological and/or pharmaceutical analysis, a capillary
electrophoresis device, a liquid chromatography device, a gas
chromatography device, an electronic measurement device, or a mass
spectroscopy device. Particularly, the fluidic device may be a High
Performance Liquid device (HPLC) device by which different
fractions of an analyte may be separated, examined and
analyzed.
[0042] The processing element may be a chromatographic column for
separating components of the fluidic sample. Therefore, exemplary
embodiments may be particularly implemented in the context of a
liquid chromatography apparatus.
[0043] The fluidic device may be adapted to conduct the mobile
phase through the system with a high pressure, for instance of 50
bar to 100 bar, particularly of at least 600 bar, more particularly
of at least 1200 bar.
[0044] The fluidic device may be adapted as a microfluidic device.
The term "microfluidic device" may particularly denote a fluidic
device as described herein which allows to convey fluid through
microchannels having a dimension in the order of magnitude of less
than 500 .mu.m, particularly less than 200 .mu.m, more particularly
less than 100 .mu.m or less than 50 .mu.m or less.
[0045] In the following, further exemplary embodiments of the
method will be explained. However, these embodiments also apply to
the flow cell and to the fluidic device.
[0046] The method may comprise forming the semiconductor oxide
tubing by converting a part of the semiconductor substrate from
semiconductor material into semiconductor oxide material, for
instance by a chemical reaction. In this context, the term
"converting" may denote that material which originally forms part
of the semiconductor substrate is treated in such a manner as to
subsequently form part of the material which represents the
semiconductor oxide material. This may be performed by thermally
oxidizing a surface portion of the semiconductor substrate, for
instance by exposing this material to a high temperature and oxygen
atmosphere, thereby converting silicon material into silicon oxide
material.
[0047] The method may further comprise forming the semiconductor
oxide tubing by thermally annealing a surface of the semiconductor
substrate. After having thermally oxidized a surface of the
semiconductor substrate, it may be advantageous or appropriate to
reduce mechanical stress in such a material by performing a thermal
annealing procedure. This may again include heating the material in
a specific atmosphere. A flow cell according to an exemplary
embodiment may be a quartz capillary which can be a small structure
susceptible to breakage which, during operation, may be subject to
high mechanical stress. It may be advantageous to take measures for
reducing stress, for instance to provide for a stress relief
structure or a flexible structure. For instance, the expansion
coefficient of silicon may differ significantly from the expansion
coefficient of silicon oxide. Hence, during conversion of silicon
to silicon oxide or later during operation of the flow cell,
mechanical stress may act on the converted material. Providing a
mechanically flexible component in the member may allow the member
to balance out such mechanical stress, thereby allowing a user to
employ the member even under harsh conditions.
[0048] The method may further comprise forming the semiconductor
oxide tubing by depositing semiconductor oxide material on a
surface of the semiconductor substrate. In such a scenario, the
semiconductor substrate may form the template or basis for the
subsequent deposition of semiconductor oxide material which, due to
the chemical similarity of semiconductor oxide (such as silicon
oxide) and corresponding semiconductor material (such as silicon)
will not generate significant mechanical stress in a boundary
portion, particularly since the lattice configurations of the
semiconductor and its semiconductor oxide are usually not too
different from one another, particularly in the case of the
material pair silicon and silicon oxide.
[0049] The method may further comprise patterning the semiconductor
substrate before forming the semiconductor oxide tubing. By such a
patterning, a recess may be formed in the semiconductor substrate
defining the geometry of the fluidic conduit. By thermally
oxidizing a surface and/or by depositing a semiconductor oxide
material subsequently onto this recess, it is possible to properly
define the geometry of the fluidic conduit simply by adjusting the
patterning procedure. Such a patterning may include the application
of lithography, particularly illumination and etching
procedures.
[0050] The method may comprise patterning the semiconductor
substrate by anisotropic etching of material of the semiconductor
substrate before forming the semiconductor oxide tubing. Such an
anisotropic etching (with etching rates being different in the
different spatial directions) may make use of an anisotropy of a
crystalline substrate regarding etching into different directions.
For instance, when a crystalline silicon substrate is etched along
a <100> crystal lattice plane, a symmetric trapezoidal recess
may be formed which can form the basis of a half hexagonal
lumen.
[0051] The method may further comprise patterning the semiconductor
substrate by mechanically weakening a selective surface portion of
the semiconductor substrate and subsequently removing the
mechanically weakened surface portion. For this purpose, DRIE (Deep
Reactive Ion Etching) may be employed.
[0052] Such a mechanical weakening may particularly be performed by
forming a comb-shaped semiconductor structure (by lithography and
etching) in a surface portion and by subsequently oxidizing the
individual fingers of the comb-shaped structure. Oxidizing a
surface portion of a silicon substrate by heat and an appropriate
chemical environment will usually affect only a surface portion of
the silicon material. When a comb structure with very small comb
elements or fingers is formed having a thickness so that the entire
finger or comb element structure is prone to conversion of silicon
material to silicon oxide material by thermal oxidizing, this may
allow to manufacture a side wall of the later flow cell.
[0053] Particularly, the method may comprise patterning the
semiconductor substrate by anisotropically etching along a
<100> plane before forming the semiconductor oxide tubing to
thereby form a trapezoidal recess in the semiconductor substrate.
This is a tricky way of defining the surface geometry of the
semiconductor substrate for a subsequent formation of the
semiconductor oxide tubing. Particularly, the semiconductor
substrate may be patterned by the anisotropic etching along the
<100> plane so that slanted side walls of the trapezoidal
recess correspond to a <111> plane of the semiconductor
substrate.
[0054] The semiconductor oxide tubing may be formed in a recess of
the semiconductor substrate formed by patterning the semiconductor
substrate. Then, two semiconductor substrates both being processed
in the described manner, i.e. both having a section of a
semiconductor oxide tubing in a recess, may be bonded in such a
manner that the recesses together form the fluidic conduit. By such
a procedure, a for instance hexagonal lumen may be enclosed by the
semiconductor substrates being bonded to one another.
[0055] The method may further comprise selectively removing a part
of the material of at least one of the two semiconductor
substrates. By taking this measure, it is possible to expose the
semiconductor oxide tubing by using a boundary between
semiconductor and semiconductor oxide as a stopping layer for a
corresponding etching procedure. Selectively removing the part of
the material of the at least two semiconductor substrates may be
performed by etching, particularly by wet etching. However, such an
etching procedure may also be performed in a chemically aggressive
gas or plasma atmosphere.
[0056] The method may comprise lining a surface, particularly an
inner surface, of the semiconductor oxide tubing with a reflection
layer adapted so that an electromagnetic radiation beam propagating
through the fluidic conduit is totally reflected at the reflection
layer. Such a lining may include properly selecting the refraction
indices of the two adjacent materials so that, in accordance with
physical laws, total internal reflection becomes possible.
[0057] Particularly, the lining may comprise conducting a lining
material through the fluidic conduit (for instance in a liquid
phase state) and subsequently solidifying, particularly by
sintering, the conducted lining material at an inner wall of the
fluidic conduit to thereby form the reflection layer. This is a
simple procedure allowing to properly define the material, the
thickness and other parameters of the inner lining.
[0058] The method may comprise forming a cover structure covering
an outer surface of the semiconductor oxide tubing, the cover
structure having a refraction index being smaller than a refraction
index of the fluidic surrounding (for instance a mobile phase, a
sample to be analyzed, etc.). By such a cover structure with the
described material properties it is possible to ensure that
internal reflection of light beams propagating through the fluidic
conduit and/or through the semiconductor oxide tubing may take
place at a boundary between the semiconductor oxide tubing and the
cover structure.
[0059] In an embodiment, the semiconductor oxide may be formed
based on the semiconductor. In other words, the semiconductor oxide
may correspond to the corresponding semiconductor material. The
semiconductor oxide may be particularly formed on the basis of the
semiconductor, by a corresponding material conversion.
[0060] Traditional UV cells are fabricated by traditional machining
methods, and are thus limited in their minimum load size. Also, the
traditional machining methods do not lend themselves well to
parallel cells of close pitch (1 mm or below).
[0061] Exemplary embodiments make use of micromachining methods to
create a total internal reflection cell, with parallel cells
allowed on the same chip. The micromachining techniques may allow
for a low cell volume, and a tight pitch. Such a cell may also be
free of reflecting metal thin films that might degrade over
time.
[0062] In the push for smaller cell size and parallelism in UV
detection systems, exemplary embodiments may employ fabrication
techniques that allow for small cell volumes and a tight pitch.
Also, being a total internal reflection cell, light may be guided
in the cell with dielectrics, without the use of metal thin films.
This may be generally believed to give a longer lasting UV
cell.
[0063] In an embodiment, micromachining techniques may be used to
build miniature UV detection cells, wherein a plurality of cells
can be fabricated from a single substrate. There may be a number of
ways to fabricate such a cell.
[0064] More generally, exemplary embodiments may provide a free
standing capillary that is clamped along a mechanically robust
frame. There in fact can be a plurality of capillaries that have a
fluid input along the mechanically robust frame, a free standing
region where detection can occur in the capillary, and a fluidic
exit along the frame. Light can be coupled into the cell by another
opening in the frame. It is also possible to provide for a
secondary fluid, other than air, and with specific dielectric
properties, to surround the capillaries. This can be realized by
bonding additional wafers to the structure.
[0065] In an embodiment, it may be advantageous to surround the
quartz capillary with air, to allow for a total reflexion of light
within the capillary. However, surrounding air under atmospheric
pressure will not contribute significantly to the mechanical
stabilization of the sensitive quartz capillary. Hence, it may be
possible to mechanically protect the quartz capillary against
mechanical damage, for instance in response to the application of
high pressure of, for instance, 100 bar. For this purpose, it may
be possible to embed the quartz capillary in a material having a
smaller refraction index than quartz. Such a surrounding medium may
be a solid, a liquid or even a gas. When using a gas (such as air
or nitrogen or a noble gas like Xenon), it is possible to provide
the gas under pressure, for instance at a pressure of 200 bar. By
applying mechanical pressure using a surrounding gas (which may be
accommodated with high pressure in a chamber surrounding the quartz
capillary) it is possible to mechanically protect the device so
that the device may be used over a broad operation range.
[0066] In an embodiment, a pressure relief valve may be provided
which can be used in a failure event causing the pressure to rise
above an allowed maximum value that the capillaries can
withstand.
[0067] A fluid may be guided through a channel formed by
semiconductor processing technology. A polychromatic light source
may emit a polychromatic light beam propagating through the fluidic
conduit so as to interact with different fractions in the fluidic
sample propagating through the channel. A spectrometer with a
grating and a photodiode array (for instance a linear line of
photodiodes) may then detect the resulting secondary light beam.
Exemplary embodiments may provide for a liquid waveguide flow cell,
particularly for liquid chromatography applications such as micro
liquid chromatography applications (<100 .mu.l/min.) or even
nano liquid chromatography applications (<1 .mu.l/min., for
instance 10 nl/min. to 500 nl/min.).
[0068] According to an exemplary embodiment, a total analysis
system in microtechnology may be provided. Thus, not only a flow
cell may be formed in a silicon wafer or a glass wafer, but it is
also possible to manufacture an integrated separation column. An
example for such an integrated column may be a pillar column. It is
also possible to combine the monolithically integrated flow cell
with a HPLC chip which can be made of polyimide material.
Alternatively, such a flow cell may also be used as a stand-alone
flow cell.
[0069] For high throughput applications, it is possible to
parallelize flow cell detection in, for instance, 8 or 10 flow
cells monolithically integrated in a single wafer.
[0070] The light conductance value of a flow cell may dramatically
decrease with increasing length of the cell. However, a smaller
light conductance value may also result in a smaller photon flow
and hence a smaller signal-to-noise ratio. In an optical system,
the smallest light conduction value defines the entire conduction
value. Larger path lengths may be realized with a total internal
reflection (TIR) based flow cell. Exemplary embodiments may also
provide for UV flow cells for the nano flow region where such an UV
flow cell might substitute conventionally used mass spectrometer
detectors.
BRIEF DESCRIPTION OF DRAWINGS
[0071] Other objects and many of the attendant advantages of
embodiments of the present invention will be readily appreciated
and become better understood by reference to the following more
detailed description of embodiments in connection with the
accompanied drawings. Features that are substantially or
functionally equal or similar will be referred to by the same
reference signs.
[0072] FIG. 1 illustrates a monolithically integrated flow cell
according to an exemplary embodiment.
[0073] FIG. 2 to FIG. 7 show layer sequences obtained during a
method of manufacturing a monolithically integrated flow cell
according to an exemplary embodiment.
[0074] FIG. 8 illustrates a pressure relief valve which can be
implemented in a monolithically integrated flow cell according to
an exemplary embodiment.
[0075] FIG. 9 illustrates a HPLC chip with a pillar configuration
which can be implemented in a monolithically integrated flow cell
according to an exemplary embodiment.
[0076] FIG. 10 to FIG. 24 show layer sequences obtained during a
method of manufacturing a monolithically integrated flow cell
according to another exemplary embodiment.
[0077] FIG. 25 and FIG. 26 show three-dimensional views of a
monolithically integrated flow cell according to an exemplary
embodiment.
[0078] FIG. 27 illustrates a liquid chromatography system according
to an exemplary embodiment.
[0079] The illustration in the drawing is schematically.
[0080] FIG. 1 illustrates a monolithically integrated flow cell 100
according to an exemplary embodiment.
[0081] FIG. 1 illustrates a cross-sectional view in a plane
parallel to a surface plane of a crystalline silicon substrate 102.
Within the silicon substrate 102, a fluidic conduit 104 is formed
which is delimited by an optically transparent silicon oxide tubing
106 which is, in turn, monolithically formed with or from the
silicon substrate 102. As can be taken from FIG. 1, the silicon
oxide tubing 106 is embedded in the semiconductor substrate
102.
[0082] The flow cell 100 further comprises for instance a light
emitting diode 108 as an electromagnetic radiation source for
generating a light beam and for coupling the light beam into a
lumen formed by the fluidic conduit 104. The flow cell 100 further
comprises an electromagnetic radiation detector 110, for instance
an optic spectrometer, comprising a linear photodiode array and a
grating. An electromagnetic radiation beam generated by the light
source 108 may be inserted into a first optical coupler element 112
such as optical fiber or an integrated waveguide, may propagate
through an optically transparent first end plate 114, may propagate
through the conduit 104 while being totally reflected at the
silicon oxide tubing 106, will propagate through a second contact
window 116 also made of optically transparent silicon oxide
material, will then propagate through a second optical coupler
element 118 in the form of a second optical fiber or an integrated
waveguide and will from there be directed into and detected by the
optical detector 110.
[0083] A first fluid supply hole 120 (extending perpendicularly to
the paper plane of FIG. 1) is formed to be in fluid communication
with the semiconductor oxide tubing 106 for supplying a fluidic
sample to the fluidic conduit 104. Although not shown in FIG. 1,
the fluid supply hole 120 is in fluid connection with an outlet of
a chromatographic column for separating different fractions of a
fluid. These different fractions may then be detected optically in
the flow cell 100.
[0084] A drain hole 122 (extending perpendicularly to the paper
plane of FIG. 1) is formed to be in fluid communication with the
semiconductor oxide tubing 106 as well for draining the fluidic
sample from the fluidic conduit 104 after having traversed the
optical and fluidic path between the fluid supply hole 120 and the
fluid drain hole 122.
[0085] In the following, referring to FIG. 2 to FIG. 7, a method of
manufacturing a flow cell 100 according to an exemplary embodiment
will be explained.
[0086] FIG. 2 shows a layer sequence 200 obtained by first
depositing a silicon oxide layer 202 on opposing exposed surface
portions of a silicon substrate 102. Then, an optional silicon
nitride layer 204 may be deposited on top of the silicon oxide
layers 202.
[0087] Subsequently, a surface portion of one of the two opposing
main surfaces of the silicon substrate 102 is exposed by patterning
the double insulating layer 202, 204 by etching to form an access
hole 302. The result is a layer sequence 300 shown in FIG. 3. After
having formed such an access hole 302, the resulting layer sequence
may be made subject of a wet etch procedure, for instance using
Potassium Hydroxide (KOH) solution for crystallographic etching of
Silicon. The consequence is that, since the etching of the
<100> wafer 102 is an anisotropic etching procedure, a
trapezoidal recess 304 is formed.
[0088] FIG. 4 shows in more detail a <100> plane and a
<111> plane of the silicon substrate 102. In order to obtain
a layer sequence 400 shown in FIG. 4, the silicon oxide layer 202
and the silicon nitride layer 204 are removed by etching
procedures. By thermally oxidizing a surface of the patterned
silicon substrate 102, a further silicon oxide layer 402 may be
formed which is optically transparent. The procedure shown in FIG.
4 can be repeated with a second wafer in a simultaneous way.
[0089] Two wafers processed in such a manner may then be connected
to one another by bonding, and a result of this is shown as a layer
sequence 500 in FIG. 5. By bonding the two wafers 400 in a way that
the recesses 304 are aligned to one another, a fluidic conduit 104
is formed which is delimited along an entire circumference thereof
by the silicon oxide tubing 106 formed by the two bonded further
silicon oxide layers 402.
[0090] By patterning (as before) and a treatment with an
appropriate chemical, for instance KOH, portions of the
semiconductor substrate 102 may be removed, thereby exposing the
fluidic conduit 106. The result is shown as a layer sequence 600 in
FIG. 6.
[0091] Optionally, a lateral section of the silicon oxide structure
106 may be removed to thereby form a fluid supply or fluid drain
hole 702, as shown in a layer sequence 700 in FIG. 7.
[0092] The layer sequence 700 is suitable for high pressure
applications of 100 bar or more. However, it may be appropriate to
provide a pressure relief valve, as the one shown in FIG. 8 and
denoted with reference numeral 800 in order to seal the various
conduits also in the presence of high pressure. For example, in the
substrate 102, a fluidic channel 802 may be formed which is open in
the scenario shown in FIG. 8. A flexible membrane 804 may be formed
over the fluidic conduit 802. By applying a pressure on the
membrane 804, the valve 802 may open, as indicated with solid lines
in FIG. 8.
[0093] The flow cells 700 or 100 may be used in combination with a
chip-like fluidic device with a chip-like separation column as
shown in FIG. 9. It is also possible to monolithically integrate
such a separation column together with the flow cell 100 or 700 in
a common substrate.
[0094] The microfluidic device 900 shown in FIG. 9 comprises a
first essentially planar member 901 and a second essentially planar
member 902. In an operation state in which the first essentially
planar member 901 is coupled to the second essentially planar
member 902 (for instance using a gluing connection to form a
laminated structure), a column tube is formed in a recess 903 which
is formed in the first essentially planar member 901 and using the
planar surface of the second essentially planar member 902 as a
lid. The recess 903 forms, when the members 901 and 902 are
connected to one another, a channel-like structure which has a
similar function as a conventional liquid chromatography separation
column.
[0095] The microfluidic device 900 can be configured and used in a
similar manner as described in FIGS. 6A and 6B and corresponding
description of US 2004/0156753 A1.
[0096] The flat surface 902 can be formed by any solvent resistant
material, including, but not limited to, polymer or glass. The
patterned polymer substrate 901 can be formed using any fabrication
technique, including embossing, laser ablation, injection molding,
etc. It should further be understood that the microfluidic device
200 can include multiple channels 903, and each channel 903 can
include a microstructured body 922 having a surface covered with
porous material 924 which can be inserted as a single piece in the
channel 903, more precisely in a central portion 905 thereof.
[0097] Optional frits 910 are arranged in end portions 904, 906 of
the recess 903 to further increase stability, but can alternatively
be omitted. As shown in FIG. 9, the channel 903 is divided into
three portions, namely a first portion 902 filled with a first frit
910, a second central portion 205 filled with a microstructured
body 920, and a third portion 908 filled with the second frit
910.
[0098] An enlarged view of a solid fluid separation member 920 to
be inserted in the channel 903 shows the microstructured body 922
in the form of parallel aligned pillars, wherein a layer of porous
material 924 covers the pillars 922. Between the pillars 922
covered with the porous layer 924, fluidic paths 926 are formed
which may also be denoted as channels. The pillars 922 are arranged
in parallel to one another and have a diameter of 3 .mu.m. The
channels 926 have a diameter of 4 .mu.m. The porous material 924
has a thickness of 0.5 .mu.m. The microstructured body 922 defines
a spatially regular pattern of the channels 926. The porous
material 924 has a uniform thickness over the entire surface of the
microstructured body 922. The pillars 922 are cylindrically shaped.
Although not shown in FIG. 9, the pillars 922 are arranged in a
matrix-like pattern. The body on the basis of which the
microstructured pillars 922 have been manufactured is a
three-dimensional substrate. Thus, all pillars 922 are connected to
one another to form one single integrally formed body. The pillars
922 may be made of silicon material and the porous layer 924 may be
made of permeable silicon oxide material.
[0099] As an alternative to the pillar arrangement 920, it is also
possible to insert fluid separation beads into the fluidic channel
905.
[0100] More generally, a flow cell according to an exemplary
embodiment may be combined with a pillar column in a common
semiconductor substrate. For instance, flow cell and pillar column
may be processed based on a shared silicon wafer. Thus, both
components may be manufactured in a shared microprocessing
environment.
[0101] In another embodiment, flow cell and pillar column may be
processed separately and may then be combined to form a hybrid-type
analysis device. In one embodiment, the pillar column may be
directly connected to the flow cell. In another embodiment, the
pillar column may be coupled to the flow cell via an adapter such
as an intermediate plate or layer. Such a layer may be for instance
sprayed on one of the components or may be a separate layer
sandwiched between the flow cell and the pillar column.
[0102] In still another embodiment, a planar column chip (such as
the polymer chip 900 for instance comprising beads or a pillar
structure) may be connected to a flow cell according to an
exemplary embodiment. Such components may be connected directly to
one another without an adapter piece in between. Such a direct
connection can be realized by a pressure seal or a bore-to-bore
connection or a plug connection. When the column chip is made of a
soft material such as a polymer material, the soft or flexible
material may provide for an efficient sealing in a leakage-free
way. A planar geometry of a column chip may fit properly with a
geometry of a flow cell. However, in another embodiment, an adapter
piece may be arranged between column chip and flow cell, for
instance as described above.
[0103] In the following, referring to FIG. 10 to FIG. 24, another
method of manufacturing a flow cell according to another exemplary
embodiment will be explained.
[0104] Starting point is a layer sequence 1000 shown in FIG. 10. A
buried silicon oxide layer 1004 is embedded between a bulk silicon
substrate 1002 and an active wafer silicon layer 1006. The active
wafer layer 1006 will define the height of the flow cell to be
manufactured, that is the cell height will be about twice that of
the thickness of the active wafer 1006. In the given example, the
active thickness is shown to be 80 .mu.m. The buried oxide layer
may be, for instance, 5 .mu.m. The width may be determined by the
layout.
[0105] On the basis of the SOI silicon substrate 1000, a comb
structure 1102 may be formed by a corresponding patterning and
etching procedure, as shown in a layer sequence 1100 illustrated in
FIG. 11. Deep reactive ion etching (DRIE) may be used to form
trenches 1104 which separate individual comb elements of the comb
structure 1102 in the active wafer layer 1006.
[0106] The comb fingers are so thin that subsequent thermal
oxidation of the layer sequence 1100 will result in a layer
sequence 1200 shown in FIG. 12 which comprises completely oxidized
silicon oxide regions substituting the former comb elements. Thus,
a silicon oxide block 1202 may be formed in a surface of the active
layer 1006 which is also covered by a silicon oxide layer 1204.
Thus, an oxidation procedure will lead to a thick oxide on the
silicon surfaces which will be thick enough to completely consume
the trenched silicon, forming the thick thermal oxide structure
1202. This technique is used to make a thick thermal oxide for
semiconductor applications.
[0107] A layer sequence 1300 shown in FIG. 13 may be obtained by
performing CMP (chemical mechanical planarization) for removing
silicon oxide material using silicon material as a stop material.
This may allow to planarize the upper surface and to remove the
silicon oxide layer 1204 from an upper surface of the layer
sequence 1200.
[0108] A layer sequence 1400 shown in FIG. 14 may be obtained by a
fusion bonding of two wafers of the type shown in FIG. 13. Two
wafers 1300 that have gone through identical processing are bonded
together, leaving a wafer structure 1400 with buried oxides of
varying thickness.
[0109] In order to obtain a layer sequence 1500 shown in FIG. 15,
the surface oxide layers 1204 are removed from the layer sequence
1400 by stripping. During such a procedure, the silicon oxide
layers 1204 on the outer surfaces of the layer sequence 1400 are
removed with HF, or any other selective etchant.
[0110] In order to obtain a layer sequence 1600 shown in FIG. 16, a
silicon etch (or polish and etch) may be performed using silicon
oxide material as stop layers. By taking this measure, the outer
silicon material of the layer sequence 1500 is removed, using a
selective silicon etchant (for instance a low pH TMAH solution).
This outer silicon may remain on some regions on the underside of
the wafer to produce added mechanical integrity.
[0111] In order to obtain a layer sequence 1700 shown in FIG. 17, a
dual sided tube oxide deposition (for instance of 5 microns) may be
performed. This may form a deposited silicon oxide layer 1702 which
is added to thicken up the pre-existing thermal oxide 1004. This
will provide added mechanical strength to the roof and floor of the
cell.
[0112] In order to obtain a layer sequence 1800 shown in FIG. 18, a
gold (Au) deposition and patterning may be performed (shadow mask
or lift off, for instance) to thereby manufacture gold contacts
1802. Thus, the gold material is deposited and patterned
selectively, and may be used for a thermo compression bond in a
later procedure.
[0113] FIG. 19 shows a layer sequence 1900 which may be obtained by
a selective silicon oxide removal procedure. Thus, vias 1902 may be
cut out in the silicon oxide material to make access for later
silicon removal.
[0114] FIG. 20 shows a layer sequence 2000 made of a glass wafer
2002 (need not be UV-transparent) which is also provided with a
patterned gold layer 2004.
[0115] FIG. 21 shows a layer sequence 2100 in which the glass wafer
2002 is wet or dry etched. Wet etching is typically quicker, but
may lead to isotropic etch profiles.
[0116] A layer sequence 2200 shown in FIG. 22 may be obtained by
power blasting or performing a further wet etch procedure. This may
be performed to create a through-hole 2202 in the glass wafer
2002.
[0117] As can be seen as a layer sequence 2300 shown in FIG. 23,
the layer sequence 1900 shown in FIG. 19 and the layer sequence
2200 shown in FIG. 22 may be bonded by gold thermo compression.
[0118] In order to obtain a layer sequence 2400 shown in FIG. 24,
silicon material previously denoted with reference numeral 1006 may
then be removed. This may create cavities 2402 for the flow cell.
For this purpose, a selective silicon etchant may be used to clear
out the silicon where required (for instance low pH TMAH or
XeF.sub.2). This leaves a cell that is only surrounded by silicon
oxide material. Silicon may remain in certain areas to provide the
frame and additional mechanical support.
[0119] Perspective views are shown in FIG. 25 and FIG. 26.
[0120] FIG. 25 shows a three-dimensional view of a flow cell 2500
in which silicon material remaining for mechanical stability is
denoted with reference numeral 2502. It does not touch sidewall
oxide. Gold for thermo compression is denoted with reference
numerals 1802, 2004. The capillary is shown and denoted with
reference numeral 104. The sidewall oxide 1202 forms part of the
silicon oxide tubing. Trench 2006 in the glass wafer 2002 is shown
as well. If desired, a plate 2002 may be additionally attached to
the bottom side of the flow cell 2500. FIG. 25 is a
three-dimensional view of a segment of a single cell 2500 that can
be one of a plurality of cells. The region where liquid is present
for analysis (analysis chamber) is surrounded only by thin
dielectrics, and this capillary 104 is prestanding in this area.
Light may be coupled at the end of the capillary (not shown in FIG.
25). Holes in the roof oxide 1702 to connect to the analysis
chamber are not shown, nor are the through holes 2202 in the glass
substrate 2002. For a practical layout, the trenches and through
holes in the glass may be displaced from the analysis chamber, with
only a very narrow trench leading to a hole in the roof oxide.
[0121] FIG. 26 shows a three-dimensional view of a flow cell 2600
according to an exemplary embodiment.
[0122] FIG. 26 illustrates a cross section near the end of the
capillary. A fluid inlet or outlet port 2602 is shown. A via to the
cell is denoted with reference numeral 2604. An end of the
capillary 2606 is shown as well. Furthermore, a silicon frame 2608
is shown. The trench in the glass is not continuous so that the
liquid of interest flows only in the cell 2600 and is not allowed
to flow over the roof along the length of the cell 2600. The trench
at the end of the cell allows liquid to get from the fluid
inlet/outlet port 2602 to the via for the cell 2600. Because some
clamping of the capillaries is required, there is a small region
where light can couple into the flow cell.
[0123] The manufactured quartz capillary (which may serve as a flow
cell) may be a mechanically sensitive structure which may be
subject to high mechanical stress during use. In order to allow for
a use of such a structure even under harsh conditions,
stress-reducing measures (for instance flex structures) may be
taken.
[0124] FIG. 27 depicts a general schematic of a liquid separation
system 2700. A pump 2720--as a mobile phase drive--drives a mobile
phase through a separating device 2730 (such as a chromatographic
column) comprising a stationary phase. A sampling unit 2740 can be
provided between the pump 2720 and the separating device 2730 in
order to introduce a sample fluid to the mobile phase. The
stationary phase of the separating device 2730 is adapted for
separating compounds of the sample liquid. A detector 100, as the
one shown in FIG. 1, is provided for detecting separated compounds
of the sample fluid. A fractionating unit 2760 can be provided for
outputting separated compounds of sample fluid.
[0125] It should be noted that the term "comprising" does not
exclude other elements or features and the "a" or "an" does not
exclude a plurality. Also elements described in association with
different embodiments may be combined. It should also be noted that
reference signs in the claims shall not be construed as limiting
the scope of the claims.
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